Neurodegenerative diseases such as Parkinson's and Alzheimer's show signs of increased oxidative stress that result when reactive oxygen species (ROS) overwhelm a cell's inherent antioxidant mechanisms. Markers of oxidative stress include lipid peroxidation, DNA base hydroxylation, and protein modification, all of which are attributed to the highly reactive hydroxyl radical, OH.. While many potential antioxidant therapies use radical scavengers in attempts to mitigate cellular damage, such strategies do not inhibit formation of these harmful radicals (See Barnham, K. J et al., Nat. Rev. Drug Disc. 2004, 3, 205-214; Jellinger, K. A., Drugs Aging 1999, 14, 115-140; Shults, C. W., Antioxid. Redox Signaling 2005, 7, 694-700; Zecca, L. et al., Nature Rev. 2004, 5, 863-873).
A principal mechanism for the formation of OH. is via iron-promoted reactions like the Fenton reaction (Eq. 1) (Dunford, H. B., Coord. Chem. Rev. 2002, 233, 311-318), which becomes catalytic if cellular reductants can reduce Fe3+ to Fe2+.Fe2++H2O2→Fe3++OH.+OH−  Eq. 1
In order for iron to promote Fenton chemistry, it must be in a coordination environment that favors redox cycling and allows reactants access to the inner sphere of the metal center (Liu, Z. D.; Hider, R. C., Coord. Chem. Rev. 2002, 232, 151-171). These requirements imply that loosely bound iron that is not properly regulated by the cell's normal metal trafficking and storage mechanisms contributes to oxidative stress. Chelating agents that can selectively sequester this pool of iron could potentially inhibit iron-promoted oxidative stress by inactivating the source itself. Although several chelators that were developed to treat iron overload diseases have some desirable properties for treating neurodegenerative diseases, they also have troubling drawbacks. Their high affinity for iron means that they compete with iron-binding proteins, thereby altering healthy iron distribution and inhibiting essential iron-containing enzymes. Furthermore, their intrinsic affinity for other metal ions disrupts the availability of key elements like zinc (Richardson, D. R., Ann. NY. Acad. Sci. 2004, 1012, 326-341; Youdim, M. B. H. et al., Ann. NY. Acad. Sci. 2004, 1012, 306-325; Kaur, D., et al., Neuron 2003, 37, 899-909; Ritchie, C. W., et al., Arch. Neurol. 2003, 60, 1685-1691; Benvenisti-Zarom, L. et al., Neuropharmacol. 2005, 49, 687-694).